This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Voltage-sensing domains (VSDs) are integral membrane proteins that sense and change conformation in response to changes in membrane electrical potential. In voltage-gated potassium (Kv), sodium and calcium channels, VSDs control the opening and closing of the ion-conducting pathway to generate electrical signals. Because of the inherit limitations of conventional crystallography, atomistic molecular dynamics (MD) simulations are essential to elucidate the structure and conformational changes of the VSD under an applied membrane electrical potential that will lead to a detailed molecular mechanism of membrane excitability. Using all-atom MD simulations on the ~100 ns time scale, we have generated structural models consistent with a variety of experimental data for the end-states of the voltage-activation process of a Kv channel VSD. However, the overall activation of a Kv channel spans time scales from 1 ?s to 1ms that are not achievable using conventional high-performance computing resources. As a next step in the structural characterization of the resting and activated states of the VSD, we propose the generation of atomistic simulation trajectories on the ~10 ?s time scale under an applied electric potential to fully sample our current end-state models and to study the conformational dynamics of fast transitions to intermediate states during the VSD voltage-dependent activation.